The road to safer painkillers: the role of the EP2 receptor

Researchers at the NYU Pain Research Center have pinpointed a receptor in prostaglandins – the hormone-like substances targeted by common painkillers – that causes pain without affecting inflammation. The findings, published in Nature Communications, could lead to the development of more selective drugs that relieve pain while minimising side effects.

Decoupling pain from inflammation

“Inflammation and pain are usually thought to go hand in hand. But being able to block pain and allow inflammation – which promotes healing – to proceed is an important step in improved treatment of pain,” said study author Nigel Bunnett, professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry and a faculty member in the NYU Pain Research Center.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, are among the most widely used medicines worldwide – with an estimated 30 billion doses consumed annually in the US alone. While these drugs effectively reduce pain, long-term use can lead to serious risks, including stomach damage and heart, kidney and liver complications.

NSAIDs work by blocking enzymes that produce prostaglandins, which reduces both inflammation and pain. However, scientists have long believed that reducing inflammation is necessary to relieve pain – a belief that may overlook inflammation’s protective role.

“Inflammation can be good for you – it repairs and restores normal function,” said study author Pierangelo Geppetti, an adjunct professor at the NYU Pain Research Center. “Inhibiting inflammation with NSAIDs may delay healing and could delay recovery from pain. A better strategy to treat prostaglandin-mediated pain would be to selectively reduce the pain without affecting inflammation’s protective actions.”

The role of EP2 receptor in pain

The study focused on prostaglandin E2 (PGE2), a key mediator of inflammatory pain, in Schwann cells. Schwann cells, located in the peripheral nervous system, play an important role in migraines and other forms of pain.

While previous research suggested the EP4 receptor as the main contributor to inflammatory pain, the NYU team used a more targeted approach and discovered that the EP2 receptor was primarily responsible for pain. Localised silencing of the EP2 receptor in Schwann cells eliminated pain responses in mice without affecting inflammation.

“To our great surprise, blocking the EP2 receptor in Schwann cells abolished prostaglandin-mediated pain but the inflammation took its normal course. We effectively decoupled the inflammation from the pain,” said Geppetti.

Further studies in human and mouse Schwann cells confirmed that activating the EP2 receptor sustains pain responses through a pathway independent of inflammatory reactions – underscoring its specific role in pain.

“Antagonism of this ‘druggable’ receptor would thus control pain without the adverse effects of NSAIDs,” said Bunnett.

Looking ahead: targeted pain therapies

The team is continuing preclinical studies to explore how drugs targeting the EP2 receptor could treat pain in conditions like arthritis – which are commonly managed with NSAIDs.

“Selective EP2 receptor antagonists could be very useful. While more research is needed on side effects, especially with giving a drug systemically as a pill, targeted administration that acts locally on an area like a knee joint holds promise,” said Geppetti.